Keywords

Myocardial infarction. Kidney. Cardiac catheterization.

Article

INTRODUCTION

Chronic renal failure has been associated with an increase in
mortality in several subgroups of patients with ischemic heart
disease; in particular, it has been shown that it worsens prognosis
in patients with ST-segment elevation myocardial infarction (STEMI)
undergoing fibrinolytic therapy1 or primary
angioplasty.2

The
development of acute renal failure (ARF) after elective cardiac
catheterization has also been associated with a poor
prognosis.3 The causes of ARF after percutaneous
coronary revascularization can be very varied, and include
contrast-induced nephrotoxicity, hemodynamic alterations,
drug-induced toxicity, or atheroembolism. A series of risk factors
for ARF have been identified during this type of procedure, such as
previous chronic renal failure, diabetes, age, volume of contrast
medium, heart failure, and periprocedural hemodynamic
alterations.4,5

On
the other hand, STEMI patients treated via urgent percutaneous
coronary intervention may be at increased risk of contrast-induced
nephropathy and ARF after catheterization compared to those
undergoing elective procedures.6 Factors that may
contribute to the development of ARF in this subgroup of patients
include hemodynamic alterations within a STEMI setting, the use of
high volumes of contrast medium, circulating volume depletion due
to sweating and vomiting, and the difficulties involved in
providing appropriate prophylaxis for contrast-induced nephropathy.
However, there are very few studies that have specifically assessed
the evolution of kidney function after urgent
catheterization.

The
aim of this study was to analyze the incidence, risk factors for,
and long- and short-term prognosis of ARF in STEMI patients
undergoing urgent percutaneous coronary revascularization, and to
design a risk classification for this complication.

METHODS

Patients

Between March 2003 and February 2007, a total of 647 STEMI patients
admitted to the emergency department of our hospital underwent 669
urgent cardiac catheterization procedures. Patients directly
transferred from other hospitals to the cardiac catheterization
unit were not included. Patients who died in the first 24 h (n=25)
were excluded as well as those in whom, for other reasons, it
proved impossible to obtain an appropriate profile of kidney
function (n=13) or chronic dialysis patients presenting terminal
renal failure (n=7). Thus, 602 patients were finally included in
the study. In the case of repeat urgent procedures for STEMI during
the study period (n=22), the first procedure was selected or the
procedure during which the patient developed ARF.

We
selected an initial cohort of 315 patients who had undergone urgent
catheterization between March 2003 and August 2005 to investigate
the predictive factors for and prognosis of ARF; a second cohort of
287 patients treated between September 2005 and February 2007 was
chosen to validate a risk classification derived from the initial
cohort.

Variables

This was a retrospective study where demographic, clinical,
angiographic, and hemodynamic variables were collected
prospectively and stored in our hospital's cardiac catheterization
unit database.

Laboratory parameters (including urea and serum creatinine
concentrations) were determined at hospital admission (prior to
beginning the procedure), and on a daily basis during patient stay
in the coronary care unit. All determinations at admission were
conducted in the hospital's emergency laboratory; all other serial
determinations were conducted in a central laboratory or in the
emergency laboratory itself.

Creatinine clearance was estimated by the Cockcroft-Gault
formula7 and the glomerular filtration rate by the
simplified MDRD (Modification of Diet in Renal Disease)
equation.8,9

Catheterization and Treatment

In
all cases, iohexol was used as the contrast agent
(Omnipaque®, Amersham Health, Carrington Hill, Cork,
Ireland). All patients received 250 mg of acetylsalicylic acid
prior to catheterization unless contraindicated. Abciximab was
administered to all patients in the emergency department or in the
cardiac catheterization laboratory prior to beginning the
procedure, except for patients who had received fibrinolytic
therapy or those presenting other contraindications. Patients
undergoing stent implantation were administered a loading dose of
300 mg of clopidogrel, followed by a daily dose of 75
mg.

The
decision to institute a hydration schedule after catheterization,
the type of fluid therapy and dose, and the need for renal
replacement therapy was left to the discretion of the physician
responsible for the patient.

Definitions

A
cardiac catheterization procedure was defined as urgent when it was
perfomed for treatment of STEMI within 12 h following symptom
onset.

Acute renal failure was defined as an increase in the absolute
concentration of creatinine ≥
0.5 mg/dL in the 72 h
following the procedure compared to creatinine concentrations at
hospital admission.10

Anemia was defined as a baseline hemoglobin concentration <13
mg/dL in men or <12 mg/dL in women.

Cardiovascular death was defined as unexplained sudden death, death
due to acute myocardial infarction (AMI), death after
rehospitalization due to heart failure, myocardial ischemia, or
death due to hemorrhagic, or embolic stroke.

Reinfarction was defined as the appearance of new symptoms of
myocardial ischemia or electrocardiographical changes, accompanied
by increases in markers of myocardial necrosis.

Follow-Up and Endpoints

Follow-up data were obtained from the hospital's databases, the
patient's medical record, and by telephone interview.

The
endpoints analyzed were total mortality and combined major
cardiovascular events (cardiovascular death, reinfarction, and
percutaneous, or surgical revascularization with objective evidence
of previous myocardial ischemia).

Statistical Analysis

Normally distributed continuous variables are presented as mean
(SD) and those with a non-normal distribution as median and
interquartile range. Discrete variables are presented as
percentages.

Comparisons between discrete variables were performed using
the χ
2 test or Fisher exact test as required, and
comparisons between continuous variables using the Student t
test or Mann-Whitney U test for those with a non-normal
distribution. The Kolmogorov-Smirnov test was used to test for
normal distribution; this was rejected for all variables except
total cholesterol.

Backward stepwise logistic regression analysis was performed to
determine the predictive factors for ARF. Variables that were
significantly associated with the development of ARF or that showed
a tendency (P<.10) toward an association were included in
the model. The variables finally included in the model were as
follows: age >65 years, sex, diabetes mellitus, hypertension,
previous chronic renal failure, treatment with
angiotensin-converting enzyme (ACE) inhibitors, and diuretic
agents, cardiogenic shock, time to reperfusion >6 h, anterior
location of infarction, anemia, creatinine concentration
≥
1.5 mg/dL, and
urea concentration ≥
50 mg/dL.

The
variables that were identified as independent predictors of ARF by
logistic regression analysis were incorporated into a risk score
where the scores assigned to each variable were determined
according to the value of the odds ratio (OR). This classification
was validated in a second cohort of 287 patients.

Death-free survival or combined events in groups with or without
ARF were compared using the Kaplan-Meier estimator (log-rank test).
Cox regression analysis was conducted to determine the predictive
factors for mortality and major cardiovascular events. Initially, a
bivariate analysis was performed followed by a multivariate
analysis which included those variables with P<.10 from
the previous bivariate analysis, as well as others considered
clinically relevant. The following variables were included in this
analysis: age, sex, smoking habit, diabetes mellitus, hypertension,
hypercholesterolemia, background of AMI, chronic renal failure,
location of the AMI, cardiogenic shock, ejection fraction,
multivessel disease, success of the procedure, time to
revascularization, anemia, fasting blood glucose concentration,
maximum troponin I concentration, creatinine concentration
≥
1.5 mg/dL, and
urea concentration ≥
50 mg/dL. A P value
less than <.05 was considered significant.

Of
the 602 patients, 72 (12%) fulfilled the criteria for ARF after
cardiac catheterization. In the initial cohort of 315 patients, 36
(11.4%) subjects developed ARF. Of this initial cohort, 266 (84.4%)
patients were men and mean age (SD) was 61 (12) years. Fifteen
(4.8%) patients were in cardiogenic shock at the time of the
procedure. Primary angioplasty comprised 96.8% of the procedures,
the remainder being urgent procedures indicated after the failure
of fibrinolytic treatment. The median (interquartile range) volume
of the contrast medium was 300 (230-393) mL.

Tables 1 and 2 show the baseline characteristics of the patients
who developed ARF compared to those who did not present this
complication. Patients fulfilling criteria for ARF were more often
women, older, and more often had a history of diabetes,
hypertension, peripheral vascular disease, and chronic renal
failure. A trend was observed in this group toward a higher
percentage of treatment with diuretics and ACE inhibitors or
angiotensin II receptor antagonists. These patients more frequently
presented with anterior AMI and were in cardiogenic shock at
admission. They also had significantly lower hemoglobin
concentrations and a worse baseline renal function
profile.

All
the variables presented similar OR values (around 3) except for
cardiogenic shock. With the aim of constructing an operational risk
score, while still taking into account the relative proportion of
the odds ratio, a value of 3 points was assigned to cardiogenic
shock and 2 points to the remaining variables; the score was
calculated as the sum of these values. The patients in the second
cohort were classified into 5 categories according to their scores
(0, 2-3, 4-5, 6-7, and ≥
8 points). Figure 1 shows the
result of this stratification in which a significant increase can
be observed in the risk of ARF per each increase in score
(P<.0001).

Figure 1.
Risk stratification for acute renal
failure (ARF) in the validation cohort according to the
score.

Prognosis of Acute Renal Failure

In-Hospital Evolution

Of
the patients who presented ARF, 22.2% (n=8) required renal
replacement therapy at admission. Continuous veno-venous
hemofiltration was employed in all these patients.

On
the other hand, ICU stay and total hospital stay were significantly
longer in the patients with ARF; in fact, the medians were double
that of the group of patients who did not present compromised renal
function (Table 4).

Long-Term Follow-Up

The
median follow-up time was 1.3 (0.8-2) years. Total mortality and
the major cardiovascular event rate were strikingly higher in the
patients who developed ARF (Figure 2). Cardiovascular mortality and
the ischemic revascularization rate were also significantly higher
in the group that presented ARF; furthermore, a nonsignificant
trend was observed toward a greater incidence of reinfarction
during follow-up in this group (Table 5). No discharged patient
required renal replacement therapy after the index hospitalization.
Finally, 3 patients in the group that developed ARF required
cardiac transplantation during follow-up, in contrast to none in
the group not presenting this complication.

Figure 2.
Kaplan-Meier curves for total
mortality and the composite endpoint of major cardiovascular (CV)
events (death, reinfarction, or revascularization) stratified
according to the development of acute renal failure
(ARF).

Although the risk of ARF after percutaneous coronary
revascularization in the general population is low (0.6%-3%,
depending on the definition used),10 the incidence can
be considerably higher in risk subgroups, especially in the setting
of STEMI; thus, Rihal et al6 identified AMI as an
independent predictor of ARF after cardiac
catheterization.

In
our study, 12% of the patients fulfilled criteria for ARF. In a
CADILLAC trial substudy,2 the reported incidence of
contrast-induced nephropathy after primary angioplasty was just
4.6%. The difference between these results and ours may be due to
the exclusion of patients with known previous renal failure or
those in cardiogenic shock, as well as to the lack of daily
measurements of renal function, given that only creatinine
concentrations at admission and discharge were assessed. Taken
together, this may have led to underestimating the true incidence
of ARF. Marenzi et al11 reported an incidence of
contrast-induced nephropathy of 19% in a group of 208 patients who
had undergone primary angioplasty.

There was a high incidence of ARF in our study even in patients
with normal renal function; in fact, 77.8% of the patients who
developed ARF had creatinine concentrations at admission <1.5
mg/dL, and 63.9% had a glomerular filtration rate of >60
mL/min/1.73 m2 assessed by the simplified MDRD equation.
It is possible that the use of a low-osmolality contrast medium may
have affected the incidence of ARF in our
study.12

Predictive Factors for Acute Renal Failure and Risk
Classification

Identifying patients at high risk of renal dysfunction after urgent
cardiac catheterization is of utmost importance, given its
prognostic implications.

However, information is limited within the setting of urgent
cardiac catheterization, given that many studies that have assessed
the predictive factors for ARF after cardiac catheterization have
excluded patients with AMI. Marenzi et al11 identified
age ≥
75
years, intraaortic balloon pump use, anterior infarction, volume of
contrast medium, and time to reperfusion as predictors of
contrast-induced nephropathy after primary angioplasty.

Baseline renal function is a strong predictor of ARF after the
procedure. Sadeghi et al2 reported an incidence of
contrast-induced nephropathy in patients undergoing primary
angioplasty which was almost 3 times higher in a group with
previous renal failure than in the cohort presenting normal
baseline renal function. In our study, baseline creatinine
concentrations ≥
1.5 mg/dL were independently associated with the
development of ARF. The baseline renal function not only depends on
creatinine concentration, but also varies with age, sex, and muscle
mass, although the estimated glomerular filtration rate or
creatinine clearance may be used for a more accurate assessment.
However, Mehran et al13 did not observe significant
differences between the models that used serum creatinine
concentration and creatinine clearance as predictors of
contrast-induced nephropathy. With the aim of obtaining a more
workable score, we decided to use serum creatinine concentration
instead of creatinine clearance. High urea concentrations were also
associated with the development of ARF. In the setting of AMI,
increased urea concentrations may reflect a renal response to
systemic hypoperfusion, rather than intrinsic renal alterations as
such.

Cardiogenic shock at admission, time to reperfusion, and anterior
AMI were also predictors of ARF. The maximum troponin I
concentrations used to estimate AMI size were also significantly
higher in the group that developed ARF. The harmful effect of
sustained hypotension on renal function is well known,4
and our results confirm that prerenal factors in a STEMI setting
play a determining role in the pathogenesis of ARF after urgent
cardiac catheterization.

Although the volume of contrast medium was higher in the group
fulfilling criteria for ARF, this association was not statistically
significant even in the univariate analysis. The volume of contrast
medium was similar to that reported in previous
studies,11 even though left ventriculography was
performed in 80% of the patients in our study. However, due to the
high incidence of ARF in these patients, it seems advisable to
avoid this whenever left ventricular function can be assessed by
alternative methods.

Prognosis of Acute Renal Failure

The
patients who developed ARF had worse in-hospital outcome; during
index admission, mortality in this group was 13.9% in contrast to
just 0.7% in the group which did not fulfill criteria for ARF.
Similarly, Marenzi et al11 reported a hospital mortality
of 31% in patients presenting compromised renal function after
primary angioplasty, in contrast to 0.6% in the population that did
not develop renal failure.

Patients who survive an episode of ARF after a percutaneous
revascularization procedure may remain at risk of long-term
events.14 In our study, total mortality and the major
cardiovascular events rate during follow-up were strikingly higher
in the group that developed ARF. Although ARF may be a marker of
hemodynamic deterioration and other comorbidities--that in turn are
important in the prognosis of these patients--it was a strong
predictor of mortality and major cardiovascular events after
adjusting for these variables.

In
the setting of primary or rescue angioplasty, standard prophylactic
treatment for ARF cannot be administered,15 and few
studies have evaluated alternative interventions in this area.
Standard hydration by saline infusion does not seem to have a
significant beneficial effect on the incidence of ARF.11
In the RAPPID16 study, a rapid protocol of intravenous
N-acetylcisteine proved effective in preventing contrast-induced
nephropathy in patients with previous renal dysfunction. In the
setting of primary angioplasty, a study reported that
N-acetylcysteine reduces the incidence of renal failure, in a
dose-dependent manner and improves in-hospital
outcome.17 In another recent study,18 a rapid
hydration protocol with sodium bicarbonate and N-acetylcisteine was
effective in preventing contrast-induced nephropathy in patients
undergoing urgent cardiac catheterization. Despite these promising
results, the need for infusing high volumes of serum during fluid
therapy in a relatively short period suggests the need for further
studies, especially in patients in cardiogenic shock or with signs
of heart failure.

Limitations

Although the demographic, clinical, angiographic, and hemodynamic
data were collected prospectively, this was a retrospective
analysis with the limitations inherent to this type of studies.
Furthermore, the small sample size may have limited the power of
our study to detect a significant association between ARF and the
volume of contrast medium. In addition, the serial analysis of
serum creatinine concentrations in 2 different laboratories may
have had an influence on assessing the incidence of ARF. Finally,
the study design makes it impossible to determine the relative
importance of atheroembolism in relation to the administration of
contrast medium or hemodynamic alterations in the development of
renal dysfunction.

CONCLUSIONS

The
incidence of ARF after urgent catheterization is high. In these
patients, diabetes, location of AMI, time to reperfusion,
creatinine and urea concentrations, and cardiogenic shock were
independent predictors of ARF. The patients who develop ARF after
urgent cardiac catheterization have a poor prognosis, with worse
in-hospital outcome, longer hospital stays, and greater long-term
mortality rates and incidence of major cardiovascular events. More
studies are needed to assess the efficacy of therapeutic
interventions designed to minimize the risk of developing ARF after
urgent cardiac catheterization.